Melanoma is a potentially lethal skin cancer. Its incidence and mortality rates are increasing faster than those of most other malignancies. The over-arching theme of this Program is melanocytic tumor progression, the process that epidemiologically, mechanistically, and clinically links environmental exposure, the precursor state, primary melanoma with and without invasive and metastatic potential, and metastasis. Our goal is to decrease mortality from melanoma, a malignancy for which there are compelling arguments for interventions directed to high risk cohorts and patients with primary disease. To achieve this, three projects will be focused on aspects of early tumor progression to: 1) define the mechanisms of and predict heightened melanoma susceptibility, 2) ameliorate this risk by rational chemoprevention, and 3) quantify the risk of metastasis in patients with primary disease to allow selection of patients for new staging procedures and adjuvant therapies. Project 1 is a case-control study that addresses the multifactorial etiology of melanoma. It asks whether candidate genotypes (ascertained from DNA self-collected using a non-invasive method) and other risk factors interact in and help explain melanoma etiology and whether these distinguish persons developing melanoma in a high risk cohort. This cohort is made up of individual s with nevi (dysplastic nevi) that are melanoma risk markers and potential precursors. Project 2 utilizes a randomized trial of topical tretinoin and 4-HPR (fenretinide) to test chemoprevention in another cohort with dysplastic nevi. It uses clinical and histologic changes in these intermediate markers of tumor progression as the endpoints and will correlate the in situ expression and distribution of retinoid receptors with response and with markers of apoptosis and of tumor infiltrating lymphocyte (TIL) activity. Project 3 employs clinical and pathological data from a cohort of patients followed for 10 years as variables in the construction and validation of credible, accurate, and generalizable prognostic models. These are a prediction rule to identify non-metastasizing lesions and a probability model to estimate individual risks of metastasis in patients with more advanced primaries. Variables include marker of melanoma cell proliferation and cytolytic TIL. These variables will also be studied in a prospective series to test as an independent variable an RT-PCR based assay for circulating melanoma cells (expression in blood of the gene for the pigment-related protein tyrosinase). To maximize productivity and efficiency the projects are served by three cores: a coordinating administrative Core, a Data Management and Analysis core, and a Pigmented Lesion Clinical/Pathology Core (PLCC). For more than 20 years the PLCC has ascertained and tracked over 4000 melanoma patients.